ORGANIC
LETTERS
2003
Vol. 5, No. 10
1649-1652
Stereoselective Entry to â-Linked
C-Disaccharides Using a Carbon-Ferrier
Reaction
Natasha Gemmell, Paul Meo, and Helen M. I. Osborn*
School of Chemistry, UniVersity of Reading, Whiteknights, Reading, RG6 6AD, U.K.
Received February 14, 2003
ABSTRACT
The synthesis of unsaturated â-linked C-disaccharides by the Lewis acid-mediated reaction of 3-O-acetylated glycals with monosaccharide-
derived alkenes is described. Deprotection and selective hydrogenation of an exocyclic carbon−carbon double, in the presence of an endocyclic
double bond, for representative targets is also illustrated.
The recognition that carbohydrates are involved in a whole
range of biological processes has provoked both the desire
to develop new methods for carbohydrate synthesis1 and the
investigation of carbohydrates as therapeutic agents.2 For
example, carbohydrates have received synthetic interest as
disease-associated targets that may prove to be of use for
vaccination programs.3 Carbohydrate analogues have also
been identified as useful glycosidase inhibitors, and as such
have proved to be of use in therapeutic strategies for the
treatment of cancer, AIDS, and diabetes.4 Such studies have,
however, identified a clear need for carbohydrate analogues
that directly mimic natural O-linked carbohydrates and offer
enhanced hydrolytic stability. In this respect, C-linked
carbohydrates have been suggested as useful synthetic targets.
A number of methods are available in the literature for
synthesizing C-linked glycosides, with some reports detailing
entry to C-linked disaccharides.5 As part of a research
program aimed at synthesizing functionalized C-linked
disaccharides, we were interested in synthesizing unsaturated
C-linked disaccharides that would offer a scope for further
functionalization to allow introduction of hydroxyl or amine
substituents, as well as hydrogenation to afford saturated
C-linked disaccharides. Previous reports6 had illustrated that
cyclohexene derivatives could be used as nucleophilic
components for carbon-Ferrier reactions7 with C-3-O-acety-
lated glycals. We were therefore keen to ascertain whether
this approach could be extended to incorporate carbohydrate-
derived alkenes to potentially allow access to C-linked
disaccharides.
At the start of this program, alkene 2 was selected as a
suitable target that may allow entry to 1,3-C-linked disac-
charides, upon reaction with a glycal, under Lewis acidic
conditions. Ketone 1 served as a key precursor to alkene 2,
via reaction with an instant ylid reagent. The ketone was
itself easily prepared from methyl-R-D-mannopyranoside via
a two-step procedure (Scheme 1).8
It is interesting to note that there is no single universal
approach for performing the Ferrier rearrangement.7 A variety
of promoters have been documented for effecting this
rearrangement, and indeed a number were studied by us in
this research program to potentially effect reaction between
alkene 2 and glycal 3. Use of SnCl4, SnBr4, TMSOTf, or
InCl3 as a promoter formed a complex mixture of products,
* Fax: +44 (0) 118 9316331.
(1) For examples of recent reviews, see: (a) Dwek, R. A.; Butters, T.
D. Chem. ReV. 2002, 102, 283. (b) Bertozzi, C. R.; Kiessling, L. L. Science
2001, 291, 2357. (c) Seitz, O. Chem. Biochem. 2000, 1, 215.
(2) Koeller, K. M.; Wong, C.-H. Nature Biotech. 2000, 18, 835.
(3) Ragupathi, G.; Coltart, D. M.; Williams, L. J.; Kiude, F.; Kagan, E.;
Allan, J.; Harris, C.; Glunz, P. W.; Livingstone, P. O.; Danishefsky, S. J.
Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 13699.
(6) (a) de Raadt, A.; Stu¨tz, A. E. Carbohydr. Res. 1991, 220, 101. (b)
Herscovici, J.; Muleka, K.; Boumaiza, L.; Antonakis, K. J. Chem. Soc.,
Perkin Trans. 1 1990, 1995.
(7) For a recent review of the Ferrier reaction, see: Ferrier, R. J. Topics
Curr. Chem. 2001, 215, 153.
(4) For example, see: Lillelund, V. H.; Jensen, H. H.; Liang, X. F.; Bols,
M. Chem. ReV. 2002, 102, 515.
(5) For some reviews, see: (a) Beau, J. M.; Gallagher, T. Topics Curr.
Chem. 1997, 187, 1. (b) Nicotra, F. Topics Curr. Chem. 1998, 187, 55.
(8) Horton, D.; Werckle, W. Carbohydr. Res. 1975, 44, 227.
10.1021/ol030023t CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/11/2003